Clostridioides difficile (formerly Clostridium difficile) infection is a substantial health and economic burden worldwide. Great strides have been made over the past several years in characterizing the physiology of C. difficile infection, particularly regarding how gut microorganisms and their host work together to provide colonization resistance. As mammalian hosts and their indigenous gut microbiota have co-evolved, they have formed a complex yet stable relationship that prevents invading microorganisms from establishing themselves. In this Review, we discuss the latest advances in our understanding of C. difficile physiology that have contributed to its success as a pathogen, including its versatile survival factors and ability to adapt to unique niches. Using discoveries regarding microorganism-host and microorganism-microorganism interactions that constitute colonization resistance, we place C. difficile within the fiercely competitive gut environment. A comprehensive understanding of these relationships is required to continue the development of precision medicine-based treatments for C. difficile infection.
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